Caffeine, metabolism

Carrillo, J. and Benitez, J., Caffeine metabolism in a healthy Spanish population N-Acetylator phenotype and oxidation pathways. Clinical Pharmacological Therapeutics 55, 293-304, 1994. 

O. Carrier, G. Pons, E. Rey, M. Richard, C. Moran, J. Badoual, and G. Olive, Maturation of caffeine metabolic pathways in infancy, Clin, Pharmacol. Ther, 44, 145 (1988). 

Levy M., Zylber-Katz E. (1983). Caffeine metabolism and coffee-attributed sleep disturbances. Clin. Pharmacol. Ther. 33, 770-5. 

Kali, M.A. and Clausen, J. (1995) Dietary effect on mixed function P450 1A2 activity assayed by estimation of caffeine metabolism in man. Human and Experimental Toxicology, 14 (10),... 

Hepatic Effects. Hepatic changes were observed in one chronic human exposure to mirex, as well as in a number of workers exposed to chlordecone for intermediate or chronic durations. In the mirex study, human subjects (sex and number not specified) from a chronically exposed cohort from southeast Ohio (route of exposure not specified, assumed to be oral) were assessed for cytochrome P- 4501A2 induction using a breath test that measures caffeine metabolism. The subjects exposed to mirex had elevated caffeine metabolism as compared to negative control individuals (subjects with no known exposure to polyhalogenated biphenyls or other related chemicals) in which the metabolism did not increase (Lambert et al. 1992). In the chlordecone study, liver function and structure in 32 men exposed to high levels of chlordecone while employed for 1-22 months (5.6... 

Hakooz N, Hamdan I (2007) Effects of dietary broccoli on human in vivo caffeine metabolism a pilot study on a group of Jordanian volunteers. Curr Drug Metab 8 9-15 Hammond DK, Bjercke RJ, Langone 11, Strobel HW (1991) Metabolism of nicotine by rat liver cytochromes P-450. Assessment utilizing monoclonal antibodies to nicotine and cotinine. Drug Metab Dispos 19 804-808... 

Tassaneeyakul W, Birkett DJ, McManus ME, et al. Caffeine metabolism by human hepatic cytochromes P450 contributions of 1A2, 2E1 and 3A isoforms. Biochem Pharmacol 1994 47(10) 1767-1776. 

Caffeine [P] Ciprofloxacin, enoxacin, pipedemic acid, and to a lesser extent, norfloxacin, inhibit caffeine metabolism. 

The phenotype for human CYP1A2 activity can be conveniently measured in vivo using caffeine as a probe drug and measuring urinary or salivary metabolite profiles. The caffeine metabolic ratio is increased in populations of smokers (31,92) and wide ranges of CYP1A2 activity have been measured in many different human studies (Table 2). 

Welfare MR, Aitkin M, Bassendine MF, Daly AK. Detailed modelling of caffeine metabolism and examination of the CYP1A2 gene lack of a polymorphism in CYP1A2 in Caucasians [published erratum appears in Pharmacogenetics 1999 Dec 9(6) 782]. Pharmacogenetics 1999 9 367-375. 

The relative safety of caffeine has lead to its widespread use as an in vivo probe for CYP1A2 activity in man. The primary route of caffeine metabolism is via N-demethylation to paraxanthine, theophylline, and theobromine. The major route of caffeine clearance in man is to paraxanthine (57). The N-3-demethylation of caffeine to paraxanthine has been shown to be mediated by CYP1A2 (58). However, paraxanthine is further metabolized to a number of different products, and as a consequence urinary metabolic ratios are often used to describe an individual CYP1A2 phenotype. 

Rost KL, Roots I. Accelerated caffeine metabolism after omeprazole treatment as indicated by urinary metabolite ratios coincidence with plasma clearance and breath test. Clin Pharmacol Ther 1994 55 402 111. 

McQuilkin SH, Nierenberg DW, Bresnick E. Analysis of within-subject variation of caffeine metabolism when used to determine cytochrome P4501A2 and N-acetyl-transferase-2 activities. Cancer Epidemiol Biomarkers Prev 1995 4 139-146. 

Table 2 Induction of C YP1 A2-dependent caffeine metabolism in herbicide workers with elevated levels of TCDD76...

Sachse S, Bhambra U, Smith G et al. (2003) Polymorphisms in the cytochrome P4501A2 gene (CYP1A2) in colorectal cancer patients and control allele frequencies, linkage disequilibrium and influence on caffeine metabolism. Br J Clin Pharmacol 55 68-76... 

Fuchs P, Haefeli WE, Ledermann, Wenk M (1999) Xanthine oxidase inhibition by allopurinol affects the reliability of urinary caffeine metabolic ratios as markers for N-acetyltransferase2 and CYP1A2 activities. Eur J Clin Pharmacol 54 869-876... 

Rodopoulos N, Wisen O, Norman A (1995) Caffeine metabolism in patients with chronic liver disease. Scand J Clin Lab Invest 55 229-242. 

Pharmacokinetics. Absorption of xanthines after oral or rectal administration varies with the preparation used. It is generally extensive (> 95%). Caffeine metabolism varies much between individuals (t/ 2-12 h). Xanthines are metabolised (more than 90%) by numerous mixed function oxidase enzymes, and xanthine oxidase. (For further details on theophylline, see Asthma.)... 

Epidemiological studies requiring further verification have suggested a relation between caffeine intake and reduced fertility, even at a consumption as low as the caffeine equivalent of more than one cup of brewed coffee a day (SEDA-14, 1). A more recent study has suggested that this reduction in fertility is limited to non-smokers possible acceleration of caffeine metabolism in smokers has been offered as a possible explanation for the apparent effect of smoking (32). 

Concern about the possible harmful effects of caffeine on the outcome of pregnancy has evolved mainly from studies of animals which have shown a reduction in intrauterine fetal growth. However, the implications of these data for men are unclear, because of the differences in mode of exposure to caffeine, the amounts consumed, and caffeine metabolism. The possible effects of caffeine intake on the human fetus have been reviewed (SEDA-7, 8) the conclusion was that the scientific data currently available could not answer the question. In an analysis of interview and medical record data in 12 205 non-asthmatic women to evaluate the relation between coffee consumption and adverse outcomes in pregnancy, the findings were negative. 

Phenylpropanolamine, which is available over the counter for weight loss, inhibits caffeine metabolism, leading to excessive stimulation for example, manic psychosis (SEDA-17,1). 

Kukongviriyapan V, Senggunprai L, Prawan A, Gaysornsiri D, Kukongviriyapan U, Aiemsa-Ard J. Sahvary caffeine metabolic ratio in alcohol-dependent subjects. Eur J Clin Pharmacol 2004 60(2) 103-7. 

CYP1A2 participates in the metabohsm of both enoxacin and caffeine, and inhibition of caffeine metabolism by enoxacin can cause adverse effects (131). 

Georga, K.A. Samanidou, V.F. Papadoyannis, l.N. The use of novel solid phase extraction sorbent materials for HPLC quantitation of caffeine metabolism products methyl-xanthines and methyluric acids in samples of biological origin. J. Chromatogr., B 2001, 759, 209 -218. 

Caffeine is rapidly absorbed after an oral dose, with peak levels reached within 1-2 h at therapeutic doses. Onset of clinical effects occurs within 60 min. In adults, caffeine is extensively metabolized by the liver primarily by N-demethylation. It is excreted in the urine primarily as 1-methyluric acid and 1-methylxan-thine. Theophylline (1,3-dimethylxanthine) is a minor product of caffeine metabolism in adults (< 1%). After massive caffeine overdoses, serum levels of theophylline are measurable. The elimination half-life of caffeine is 3-6 h at therapeutic doses. The half-life is shorter in smokers and is prolonged by oral contraceptives, cimetidine, late pregnancy, and in overdose. The half-life of caffeine is much longer in infants and does not approximate that seen in adults until 6 months of age. The half-life of caffeine may exceed 100 h in preterm infants. Only 1-10% of caffeine appears unchanged in the urine in adults. Neonates may excrete up to 85% of caffeine unchanged. 

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